Risedronate sodium [1-hydroxy-3-(3-pyridinyl)ethylidene-bisphosphonic acid sodium salt] is known to be useful in the treatment of diseases, like osteoporosis, characterized by progressive loss of bone mineral and architectural deterioration of bone tissue. The present inventors have observed that risedronate sodium is prone to pick-up or retain metals, especially iron, during synthesis and work-up.
Phosphonates, i.e. compounds containing one or more groups of structure C—P(O)(OH)2, can function as chelating agents. A chelating agent is a multidentate ligand. It simultaneously attaches to two or more positions in the coordination sphere of the central metal ion. Without being held to any theory of operation, the present inventors believe that risedronate sodium can act as a chelating agent, which contributes to the pick-up and retention of metals, especially iron.
Residual iron is unnecessary and does not contribute to the pharmacological efficacy of risedronate sodium. Residual iron correlates with yellowness in the product, which is an undesirable quality in a pharmaceutical compound. Clearly, there is a need for methods to obtain sodium risedronate with a very low content of residual iron and with a corresponding excellent color.
Risedronate sodium is also capable of existing in several polymorphic or pseudopolymorphic forms. The polymorphs and pseudopolymorphs can be influenced by controlling the conditions under which the salt is obtained in solid form, for example by controlling conditions of crystallization. Solid state physical properties that can differ from one polymorph (or pseudopolymorph) to the next include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must take that fact into account in developing a tablet or capsule formulation, which may necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate. Clearly, discovery of new polymorphs or pseudopolymorphs and control of polymorphic form are desirable.